Zanubrutinib Shows Superior PFS vs Venetoclax/Obinutuzumab in Indirect Comparison of Treatment-Naive CLL

Findings from an indirect comparison of treatment-naive patients with chronic lymphocytic leukemia (CLL) treated in the phase 3 SEQUOIA trial (NCT03336333) and the phase 3 CLL14 trial (NCT02242942) demonstrated that zanubrutinib (Brukinsa) produced significantly longer investigator-assessed progression-free survival (PFS) compared with fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva), according to data published in Oncology and Therapy.1

After matching and adjustment for baseline characteristics between the zanubrutinib (n = 163) and venetoclax/obinutuzumab groups (n = 216) from the CLL14 population, zanubrutinib demonstrated significantly longer investigator-assessed PFS compared with venetoclax plus obinutuzumab (HR, 0.66; 95% CI, 0.44–0.97; P = .0351), with 60-month landmark PFS rates of 73.9% and 63.0%, respectively. Additionally, consistent benefits with zanubrutinib were observed in the unmatched intent-to-treat population, and these findings were maintained following sensitivity analyses controlling for COVID-19–related adverse effects and other baseline variables.

“In the absence of head-to-head trials and data from prospectively designed clinical trials, indirect comparisons can provide valuable information regarding the comparative efficacy and safety of treatments,” lead study author Talha Munir, MBChB, PhD, of Leeds Teaching Hospitals NHS Trust, and coauthors wrote in the analysis. “On the basis of the efficacy and safety results of our analyses, continuous therapy with zanubrutinib in [patients with] treatment-naive CLL/[small lymphocytic lymphoma (SLL)] remains a valuable treatment option compared with fixed-duration venetoclax plus obinutuzumab.”

What Was the Methodology for the Matching-Adjusted Indirect Comparison of Zanubrutinib and Venetoclax Plus Obinutuzumab?

This study utilized a matching-adjusted indirect comparison (MAIC) methodology to evaluate the efficacy and safety of zanubrutinib vs venetoclax plus obinutuzumab in treatment-naive patients with CLL or SLL. Outcomes of interest included PFS, overall survival (OS), safety, and adverse effects of interest (AEIs).

Individual patient data (IPD) for zanubrutinib were obtained from arms A and C of the SEQUOIA trial. Comparator data for venetoclax plus obinutuzumab were extracted from published results of the CLL14 trial. For efficacy analyses, 5-year follow-up data from CLL14 were used, with a median follow-up of 65.4 months. Safety analyses were based on 2 published datasets, including results with a median follow-up of 28.1 months and at least 2 years post-treatment, with a median follow-up of 39.7 months.

MAIC methodology integrates IPD from one study with aggregate-level data from another, adjusting for differences in baseline characteristics to generate weighted treatment effect estimates. In this unanchored MAIC, IPD from SEQUOIA were weighted to balance key prognostic and effect-modifying factors with the CLL14 population.

Baseline variables selected for matching included:

• Demographics: age, sex
• Genetics: IGHV mutation status
• Clinical status: ECOG performance status, CLL/SLL proportion, disease stage, β2 microglobulin, creatinine clearance, B symptoms, and time from diagnosis

Since the SEQUOIA trial was conducted during the COVID-19 pandemic, whereas CLL14 was not, exploratory analyses censoring for COVID-19–related deaths were performed to reduce potential bias in efficacy and survival outcomes.

What Were the Baseline Patient Demographics in the Analysis?

In the unadjusted SEQUOIA intent-to-treat (ITT) population (n = 352), the median patient age was 70 years, with 26.7% aged 75 years or older.2 Following matching and adjustment (effective sample size = 163), the median age was 72 years, with 33.3% of patients aged 75 years or older.1 These values were consistent with the venetoclax plus obinutuzumab arm from the CLL14 trial (n = 216), where the median age was also 72 years, and 33.3% of patients were aged 75 years or older.3 The sex distribution was similar across arms, with approximately 2/3 of patients being male (SEQUOIA ITT, 66.2%; post-matching, 67.6%; CLL14, 67.6%).1

Prior to adjustment, 31.8% of patients in SEQUOIA carried a del17p abnormality, compared with 8.1% in CLL14. Matching reduced this imbalance, with 8.1% of patients in the adjusted SEQUOIA population harboring del17p. Similarly, frequencies of del11q (17.1%), trisomy 12 (17.1%), and TP53 mutation (12.0%) were balanced between the adjusted SEQUOIA and CLL14 populations. The rate of IGHV mutation was 43.0% in the SEQUOIA ITT cohort, decreasing to 38.6% after matching, which was identical to CLL14 (38.6%).

In the unadjusted SEQUOIA ITT population, 8.2% of patients had an ECOG performance status of 0 to 2, compared with 13.0% in both the adjusted SEQUOIA and CLL14 cohorts. Distribution by Binet stage also shifted after matching, with stage C disease rising from 31.0% in SEQUOIA ITT to 43.5% in the adjusted cohort and in the CLL14 cohort (43.5%). The prevalence of B symptoms was 57.1% in SEQUOIA ITT, compared with 48.0% in the adjusted cohort and CLL14. Median time from diagnosis to treatment initiation was 29 months in the SEQUOIA ITT population and 31 months in both the adjusted SEQUOIA and CLL14 groups.

Baseline laboratory features were also comparable after matching. In SEQUOIA ITT, 62.7% of patients had β2-microglobulin greater than 3.5 mg/L compared with 59.4% in both the adjusted SEQUOIA and CLL14 populations. Median β2-microglobulin levels were 4.0 mg/L in SEQUOIA ITT vs 3.9 mg/L in both adjusted SEQUOIA and CLL14. Baseline creatinine clearance was lower in SEQUOIA ITT, with a median of 70.0 mL/min, and 48.3% was less than 70 mL/min, although balanced to 65.6 mL/min (59.5% <70 mL/min) in the adjusted cohort, identical to CLL14.

What Were the Outcomes of the Safety Analysis?

After weighting, the incidence of any-grade treatment-emergent adverse effects (TEAEs) occurred in 96.3% of patients treated with zanubrutinib in the overall period compared with 94.8% treated with venetoclax plus obinutuzumab at a median of 170 weeks. Grade 3 or 4 AEs occurred in 64.4% and 70.8%, respectively.

Hematologic toxicities were less frequent in the zanubrutinib arm. In the zanubrutinib group and the venetoclax plus obinutuzumab group, respectively,neutropenia was observed in 10.3% of patients vs 52.8%, decreased neutrophil count was observed in 2.8% vs 4.2%, thrombocytopenia in 1.7% vs 13.7%, and febrile neutropenia at 0.9% vs 5.2%.

The incidence of any serious TEAE was 57.0% with zanubrutinib vs 54.0% with venetoclax plus obinutuzumab. TEAEs leading to death occurred in 7.7% vs 9.0%, and TEAEs resulting in treatment discontinuation occurred at 18.8% vs 15.6%, respectively.

Median treatment duration was 61.2 months in SEQUOIA for zanubrutinib vs 11.1 months in CLL14 for venetoclax plus obinutuzumab, with median follow-up durations of 62.7 and 39.7 months, respectively.

“Findings from this study may help inform clinical treatment sequencing and patient preferences to optimize clinical decision-making and improve health economic modeling,” the coauthors wrote. “Future studies are important to better understand the roles of fixed versus continuous duration in different patient populations, including sex, race/ethnicity, age, and medical comorbidities. In addition, further research is warranted to explore other outcomes, including quality of life, disability, and cost-effectiveness.”

References

1. Munir T, Martinez-Calle N, Xu S, et al. Indirect Comparisons of the Efficacy and Safety of Zanubrutinib versus Venetoclax plus Obinutuzumab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Oncol Ther. Published online September 13, 2025. doi: 10.1007/s40487-025-00380-0
2. Shadman M, Munir T, Robak T, et al. Zanubrutinib versus bendamustine and rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma: median 5-year follow-up of SEQUOIA. J Clin Oncol. 2025;43(7):780–7.
3. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924–35.